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Lack of disease during chronic human cytomegalovirus (CMV) infection depends on the maintenance of a high-frequency CMV-specific T cell response. The composition of the T cell receptor (TCR) repertoire underlying this response remains poorly characterised, especially within African populations in which CMV is endemic from infancy. Here we focus on the immunodominant CD8+ T cell response to the immediate-early 2 (IE-2)-derived epitope NEGVKAAW (NW8) restricted by HLA-B*44:03, a highly prevalent response in African populations, which in some subjects represents >10% of the circulating CD8+ T cells. Using pMHC multimer staining and sorting of NW8-specific T cells, the TCR repertoire raised against NW8 was characterised here using high-throughput sequencing in 20 HLA-B*44:03 subjects. We found that the CD8+ T cell repertoire raised in response to NW8 was highly skewed and featured preferential use of a restricted set of V and J gene segments. Furthermore, as often seen in immunity against ancient viruses like CMV and Epstein-Barr virus (EBV), the response was strongly dominated by identical TCR sequences shared by multiple individuals, or "public" TCRs. Finally, we describe a pair "superdominant" TCR clonotypes, which were germline or nearly germline-encoded and produced at remarkably high frequencies in certain individuals, with a single CMV-specific clonotype representing up to 17% of all CD8+ T cells. Given the magnitude of the NW8 response, we propose that this major skewing of CMV-specific immunity leads to massive perturbations in the overall TCR repertoire in HLA-B*44:03 individuals.

Original publication

DOI

10.3389/fimmu.2018.02539

Type

Journal article

Journal

Front Immunol

Publication Date

2018

Volume

9

Keywords

HLA-B*44:03, T cell, T cell receptor, cytomegalovirus, repertoire, sequencing, Adult, African Continental Ancestry Group, CD8-Positive T-Lymphocytes, Cytomegalovirus, Cytomegalovirus Infections, Epitopes, T-Lymphocyte, Flow Cytometry, HLA-B44 Antigen, High-Throughput Nucleotide Sequencing, Humans, Immediate-Early Proteins, Immunity, Cellular, Immunodominant Epitopes, Male, Peptides, Receptors, Antigen, T-Cell, South Africa, Trans-Activators, Young Adult